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Article: Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor

TitleTargeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor
Authors
Issue Date2014
Citation
Journal of the American Chemical Society, 2014, v. 136, n. 17, p. 6355-6361 How to Cite?
AbstractA working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)exp. It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)exp interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. Ligand 3 binds r(CUG)12 with a low micromolar affinity (Kd = 8 ± 2 μM) and disrupts the MBNL1-r(CUG)12 interaction in vitro (Ki = 8 ± 2 μM). In addition, ligand 3 is cell and nucleus permeable, exhibits negligible toxicity to mammalian cells, dissolves MBNL1-r(CUG)exp ribonuclear foci, and restores misregulated splicing of IR and cTNT in a DM1 cell culture model. Importantly, suppression of r(CUG)exp RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1. © 2014 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/336124
ISSN
2023 Impact Factor: 14.4
2023 SCImago Journal Rankings: 5.489
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWong, Chun Ho-
dc.contributor.authorNguyen, Lien-
dc.contributor.authorPeh, Jessie-
dc.contributor.authorLuu, Long M.-
dc.contributor.authorSanchez, Jeannette S.-
dc.contributor.authorRichardson, Stacie L.-
dc.contributor.authorTuccinardi, Tiziano-
dc.contributor.authorTsoi, Ho-
dc.contributor.authorChan, Wood Yee-
dc.contributor.authorChan, H. Y.Edwin-
dc.contributor.authorBaranger, Anne M.-
dc.contributor.authorHergenrother, Paul J.-
dc.contributor.authorZimmerman, Steven C.-
dc.date.accessioned2024-01-15T08:23:41Z-
dc.date.available2024-01-15T08:23:41Z-
dc.date.issued2014-
dc.identifier.citationJournal of the American Chemical Society, 2014, v. 136, n. 17, p. 6355-6361-
dc.identifier.issn0002-7863-
dc.identifier.urihttp://hdl.handle.net/10722/336124-
dc.description.abstractA working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)exp. It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)exp interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. Ligand 3 binds r(CUG)12 with a low micromolar affinity (Kd = 8 ± 2 μM) and disrupts the MBNL1-r(CUG)12 interaction in vitro (Ki = 8 ± 2 μM). In addition, ligand 3 is cell and nucleus permeable, exhibits negligible toxicity to mammalian cells, dissolves MBNL1-r(CUG)exp ribonuclear foci, and restores misregulated splicing of IR and cTNT in a DM1 cell culture model. Importantly, suppression of r(CUG)exp RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1. © 2014 American Chemical Society.-
dc.languageeng-
dc.relation.ispartofJournal of the American Chemical Society-
dc.titleTargeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/ja5012146-
dc.identifier.pmid24702247-
dc.identifier.scopuseid_2-s2.0-84899736950-
dc.identifier.volume136-
dc.identifier.issue17-
dc.identifier.spage6355-
dc.identifier.epage6361-
dc.identifier.eissn1520-5126-
dc.identifier.isiWOS:000335369200039-

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